Bio

Academic Appointments

Contact

Research & Scholarship

Current Research and Scholarly Interests

High flux dialysis in in-vivo and in-vitro clearances, of small and middle molecular weight solutes; computerized capture, of interdialysis hemodynamics; biocompatibility of biomembranes;, dialysis-related amyloidosis

All Publications

Abstract

Nephrogenic systemic fibrosis is a disabling progressive condition that is being reported with increased frequency in patients with kidney disease. Treatment is extremely limited and largely supportive. We report a case of severe nephrogenic systemic fibrosis in a dialysis patient exposed to multiple doses of gadolinium who improved clinically and histologically with treatment with imatinib.

Abstract

Recent Occupational Safety and Health Administration guidelines require the implementation of needleless systems in dialysis units in the state of California. It is not known whether needleless systems deliver medication as well as traditional low dead-space needle/syringes. The purpose of this study was to compare the delivery of recombinant human erythropoietin (rHuEpo) by a needleless system (Medic Plastic Anti-Stick Needle/Connector, Medisystems, Seattle, WA) with delivery using a traditional low dead-space needle/syringe. We also studied the Medisystems High Flow venous chamber with integral injection site that is designed to prevent the formation of a separate serum layer within which rHuEpo may become trapped. There was no significant difference in the mean serum rHuEpo concentration achieved by either the needleless system, or traditional low dead-space needle/syringe, whether using the venous chamber's integral injection site or the postvenous chamber in-line injection site. This study demonstrates for the first time that a needleless system of delivery can reliably achieve serum rHuEpo comparable to traditional low dead-space needle/syringes.

Abstract

Transplant renal artery stenosis (TRAS) is an increasingly recognized complication of renal transplantation, with a reported incidence of between 1% and 23%. The clinical features include refractory hypertension, new-onset hypertension, allograft dysfunction, and the presence of a bruit over the graft. In this report, we describe the investigation and treatment of one such patient and review the current diagnostic approaches and therapy in this setting.

Abstract

Serum concentrations of rHuEPO were measured after injection into different sites within the blood lines in patients undergoing hemodialysis. The authors compared the venous port to venous drip chamber injection using two separate delivery systems and their associated blood lines (Cobe Centry 3 [CGH, Lakewood, CO] and Fresenius A2008 [Fresenius USA, Concord, CA]). The former has a unique cartridge drip chamber and the latter a more conventional set-up. Patients were injected at both sites with their usual dose of rHuEPO at the beginning of dialysis and plasma levels were measured throughout dialysis. Significantly lower plasma levels occurred only after injection into the venous drip chamber using the Fresenius delivery system. Simultaneous samples were drawn from the venous and arterial ports and upper and lower drip chamber in a group of patients dialyzing on this system. Levels were 26 and 32 times higher in the upper and lower drip chamber compared to the venous sample, which exceeded the arterial sample. No significant rebound of rHuEPO was detected at the end of dialysis after saline rinse back in patients in whom the rHuEPO was injected into the drip chamber. The authors conclude that injection of erythropoietin into the venous drip chamber of the Fresenius delivery system should be avoided because substantial quantities are lost by "trapping," and not eluted at the end of dialysis.

Abstract

Use of iodinated contrast for vascular imaging can be associated with nephrotoxicity and hypersensitivity reactions. Renal injury following conventional angiography is more likely to manifest in the setting of preexisting renal dysfunction. In the setting of suboptimal renal allograft function, these considerations are particularly relevant. Recently, CO2 has received attention as a nontoxic, injectable, rapidly absorbed gas that is a cost-effective alternative to standard contrast agents in high-risk patients, such as renal transplant recipients. We report the clinical course of a patient with transplant renal artery stenosis and a serum creatinine of 2.8 mg/dl who has successfully undergone angiography and percutaneous transluminal angioplasty using CO2 as the sole contrast agent. This case illustrates the potential use for CO2 as a contrast agent for vascular imaging in patients with suboptimal renal function who require definitive vascular imaging or therapy.

Abstract

The pharmacokinetics of intravenous recombinant erythropoietin administered during or after dialysis were studied by multicompartmental analysis in eight patients with end-stage renal disease to determine whether significant loss of the drug occurred during the hemodialysis procedure. Each patient had five studies, one in which the erythropoietin was given near the end of a dialysis session (baseline). In the other studies, erythropoietin was administered at the beginning of hemodialysis for 4 hrs using each of four different dialysis membranes. Both two compartment and three compartment models were used. In the two compartment solutions, the mass of the exchange compartment was significantly increased in the studies done during dialysis compared with the baseline. Clearance did not change significantly among the study sessions. When a third compartment, representing the dialysis system, was added, the kinetics of the internal exchange compartment and of the dialysis system could be determined separately. At the end of 4 hrs of dialysis after the erythropoietin dose, the dialysis systems contained an average of 7% of the administered dose. It was concluded that hemodialysis immediately after erythropoietin administration does not affect the rate of erythropoietin loss, except for small losses in the dialysis system itself when it is removed at the termination of the procedure.

Abstract

Despite the widespread long practice of reuse there is continued criticism of the technique both in the media, journals and more recently at specially convened meetings. In the United States there are three principal sterilant/germicides used in reprocessing hemodialyzers: peracetic acid, formaldehyde and glutaraldehyde. The use of peracetic acid now exceeds that of formaldehyde while the more recent development of heat sterilization is only practiced in a few units. The major advantages of reprocessing include reduced cost, reduced first use syndrome and intradialytic symptoms which may be a result of increased biocompatibility with reuse. There is little data with regard to hospitalization and the recent reports of mortality rates are discussed. The major disadvantages associated with reprocessing include risks of infection, chronic exposure and accidental exposure to patients and staff to the sterilant germicide. We conclude that the reuse of dialyzers continues to be appropriate provided units follow the manufacturer's guidelines, the AAMI Recommended Practices and have a method in place to ensure the prescribed dialysis prescription is delivered.

Abstract

Between March 1981 and November 1992, 100 heart-lung transplantations were performed at our institution. We report on the renal function in the 67 patients who survived a minimum of 6 months posttransplantation, and who were aged more than 10 years at the time of transplant. Renal function was determined by serial measurement of serum creatinine. Mean serum creatinine increased from 0.96 +/- 0.03 mg/dL at baseline to 1.55 +/- 0.07 mg/dL at 6 months posttransplantation, to 1.88 +/- 0.11 mg/dL at the end of follow-up (mean follow-up, 50.0 months; range, 6 to 140 months). The decline in renal function was biphasic, with a rapid decrease in the first 6 months, followed by a much slower decline. Three patients developed end-stage renal failure. This compares with 14 of 416 cardiac transplant recipients at Stanford who developed end-stage renal failure over the same period. We conclude that in our large series at a single center the incidence of renal impairment and end-stage renal failure is low and similar between heart-lung and heart transplant patients.

Abstract

Metastatic papillary carcinoma was diagnosed in a 42-year-old woman. The cancer had invaded out of the gland and was present in many lymph nodes. After her surgical procedure, she was advised to have radioiodine. However, the patient had total renal failure and was on dialysis. Studies were carried out using a tracer dose of 2 mCi of radioiodine, demonstrating that approximately 60% of the radioactivity in the body was removed with each dialysis. Calculations indicated that a meaningful dose of radiation could be delivered to residual thyroid and metastases with 100 mCi of radioiodine and the total body radiation would be < 100 rad delivered over several days. Based on these analyses, she received 100 mCi of I-131 on two separate occasions and on follow-up scan, clinical evaluation and thyroglobulin measurement is free of disease.

Abstract

Acute renal failure can occur in cardiac transplant patients for a variety of reasons. A case of a patient who developed acute renal failure secondarily to drug-induced rhabdomyolysis is reported. The literature regarding acute renal failure and lovastatin and other 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors is reviewed. The potential mechanisms of myoglobinuria and nephrotoxicity and the therapeutic implications are discussed.

Abstract

beta 2-Microglobulin (beta 2-M) deposits have been found in the destructive bone lesions associated with dialysis-related amyloidosis. To examine whether beta 2-M can cause bone resorption in vivo, doses of beta 2-M alone were compared with parathyroid hormone (PTH), aluminum, and vehicle alone. Eleven injections of 10 micrograms each were made over a period of 56 hours into the subcutaneous tissue overlying the occipital region of mice. Using a computerized image analysis system we measured (1) periosteal and inner bone length, (2) bone marrow interface length, and (3) the extent of resorption along these surfaces expressed as percentage of total length. Injections of either beta 2-M or PTH were associated with 22% +/- 4% and 25% +/- 4% resorption of periosteal surface, respectively, and 15.9% +/- 2% and 19.9% +/- 5% resorption of marrow bone surfaces, respectively, compared with control. In contrast, aluminum did not increase bone resorption over controls. The simultaneous injection of calcitonin, an osteoclast inhibitor, with beta 2-M or PTH did not increase periosteal resorption over controls. The resorption of inner bone surface was similar in all groups. These studies show that beta 2-M and PTH cause bone resorption in the bone surfaces proximate to the site of injection. This suggests that beta 2-M may contribute to the development of the bone cysts in dialysis-related amyloidosis.

Abstract

The use of high-flux dialysis in clinical practice increased rapidly despite an absence of reports on the clinical effectiveness of the technique. Mortality and hospital admission rates of patients treated with high-flux dialysis were evaluated and compared with those of patients treated with conventional dialysis in a hospital-based renal dialysis unit in northern California. By use of a retrospective, cross-over design, 253 patients enrolled in the dialysis unit from January 1987 to January 1991 were studied. During this period, 107 patients were treated with high-flux dialysis for at least 1 month, and all but 17 of them had received conventional dialysis before switching to high-flux dialysis. The remaining 146 patients were treated with only conventional dialysis. Of the 80 patients who died during the study period, 69 were receiving conventional dialysis and 11 were receiving high-flux dialysis. The multivariate analyses, adjusted for age, gender, ethnic background, type of renal failure, comorbid conditions, and duration of ESRD, showed that annual mortality was substantially less for patients treated with high-flux dialysis compared with that for patients treated with conventional dialysis (7 versus 20%; P < 0.001). The difference in the rate of hospital admissions was not statistically significant. In this nonexperimental study, methods were applied to control for selectivity bias and other factors that might confound the apparent treatment effect. The findings suggest that the potential benefits of high-flux dialysis are sufficient to justify further confirmation in a randomized, controlled trial.

Abstract

We have developed an in vivo pressure monitoring system to study the phenomenon of reverse ultrafiltration of dialysate during high-flux and high-efficiency dialysis. Under the usual operating conditions of either type of dialysis, driving pressures existed for reverse ultrafiltration of dialysate into the venous end of the blood compartment. Whether or not reverse ultrafiltration could be abolished at higher ultrafiltration rates was dialyzer-dependent, being least with high-efficiency dialysis. In addition, the degree of reverse ultrafiltration was affected by patients hematocrit, dialyzer inlet and outlet oncotic pressures, and the rate and direction of dialysate flow.

Abstract

We developed a model that predicts the hemodynamics of the volumetrically-controlled circuit used to administer high flux hemodialysis. The equations simulate the entire blood side of the circuit so that blood and dialysate pressures can be predicted from a knowledge of circuit component and patient characteristics. An alternative method of computation has also been devised which permits measured circuit pressures to be used to predict patient blood access pressure, dialyzer resistance to flow and membrane hydraulic conductivity. Success of the model was evaluated by measuring both circuit pressure and component characteristics. The model successfully predicted circuit pressures when measured component characteristics were employed as model inputs. Conversely, the model accurately predicted circuit component characteristics when measured pressures were employed as inputs (8 patients, 30 dialyses). Specific predictions of the model include the following. Elevations of patient blood access pressure will cause blood and dialysate pressures to rise equivalently without affecting the rate of back-filtration or location of pressure equilibrium along the dialyzer axis. Elevated hematocrit is predicted to increase circuit pressures to a degree that is similar to a poorly functioning blood access, however, high hematocrit markedly augments back-filtration and moves the point of pressure equilibrium toward the dialyzer entrance. We conclude that the model provides a predictive tool that can be used to optimize circuit design. Alternatively, the model can be used to separate the influence of a poorly functioning patient access from other factors which can elevate circuit pressures.

Abstract

Cost-effectiveness analysis is emerging as an approach for determining the relative value of health care programs, technologic innovations, and clinical decisions. Increasingly, patients' stated values for quality of life are applied as adjustment in these analyses; the results may vary depending on how individuals assess their well-being. We interviewed 58 patients with chronic renal failure to determine the level of agreement among six methods for assessing well-being, and to determine the effects of variation in assessed well-being on the results of a cost-effectiveness analysis of in-center hemodialysis. Patients reported well-being using the Sickness Impact Profile, Campbell Index of Well-being, Kaplan-Bush Index of Well-being, categorical scaling, standard gamble, and time trade-off. We found that patient well-being was substantially higher as evaluated by the Sickness Impact Profile compared to the other five methods. The Sickness Impact Profile and the Kaplan-Bush Index of Well-being provided much narrower distributions of assessed values relative to other measures. Correlations among assessment methods were poor (Spearman rank-correlation coefficients range: 0.094-0.519). Discrepancies among indices were particularly vivid when we evaluated data at the individual level; many patients reported a high level of well-being according to one index and a low level of well-being according to a different index. The cost effectiveness of in-center hemodialysis varied from $34,893 to $45,254 per quality-adjusted life-year saved according to the Sickness Impact Profile and standard-gamble technique respectively. The substantial variability in patients' stated quality of life may preclude the use of a single method to analyze the cost effectiveness of a health program.

Abstract

To further define the relationship between dialyzer reuse and the removal of beta 2-microglobulin (beta 2M) during dialysis, 26 patients who received hemodialysis were studied. Thirteen patients were dialyzed with conventional cuprophane dialyzers, and thirteen patients were dialyzed with high-flux polysulfone dialyzers. Patients in each group were dialyzed with only new dialyzers during the primary-use phase of the study, and reprocessed dialyzers during the reuse phase. Dialyzers were used six times during the reuse phase. Serum beta 2M levels were measured both predialysis and postdialysis, and adjusted for fluid loss. Dialysis with conventional cuprophane new dialyzers during the primary-use phase of the study resulted in a 3.3% increase in serum beta 2M levels, and a 2.4% increase in serum beta 2M levels during the reuse phase. The difference in the change of the concentration of beta 2M between primary-use and reuse phases was not statistically significant. Dialysis with high-flux polysulfone new dialyzers during the primary-use phase was associated with a decrease of 59.5% in the mean postdialysis concentration of serum beta 2M compared with the predialysis level. A corresponding decrease of 62.6% in serum beta 2M levels was observed after dialysis with high-flux polysulfone reprocessed dialyzers during the reuse phase. These data show no evidence of an adverse effect on the clearance of beta 2M during dialysis from the reuse of dialyzers up to six times. The results confirm previous studies that have reported that high-flux dialysis with polysulfone dialyzers removes substantial amounts of beta 2M, and dialysis with conventional cuprophane dialyzers does not.

Abstract

The clearance of urea and beta 2-microglobulin are important considerations along with biocompatibility in selecting membranes for use in shortened dialysis. During 3 hr of dialysis we have measured the in vivo urea clearances, pre- and post-beta 2-M levels, plasma clearance and simultaneous dialysance of beta 2-M. Leucopenia was compared after 15 min of dialysis on a cellulose acetate (CA) dialyzer and a polyacrylonitrile dialyzer (PAN). Clearance of urea was similar in both dialyzers. In contrast to CA, PAN removed beta 2-M and exhibited minimal leucopenia. The dialysance of beta 2-M was significantly less than the simultaneous blood side clearance. The disparity between blood clearance and dialysance by PAN membranes suggests removal of beta 2-M by adsorption and diffusion. We conclude that in comparison with CA dialyzers, PAN membranes remove beta 2-M, have equivalent urea clearances, and are more biocompatible.

Abstract

We have developed a mathematical model that predicts the performance of continuous arteriovenous hemodialysis. Given patient (plasma protein concentration, hematocrit, mean arterial pressure, central venous pressure) and circuit (flow resistance, membrane hydraulic permeability, dialyzer mass transfer coefficient, ultrafiltrate column height, dialysate flow rate) characteristics as inputs, predictions of hydraulic and oncotic pressure distribution, filtration rate, blood flow, total, diffusive, and convective urea clearances are provided. The model was tested by perfusing a circuit with bovine blood under conditions of pure ultrafiltration, zero net ultrafiltration and dialysis, or combined ultrafiltration and dialysis (countercurrent dialysate flow at rates of 10, 20, and 30 ml/min). In order to permit computation, membrane hydraulic permeability and flow resistances were measured. Dialyzer mass transfer coefficient for urea could not be measured directly and so was determined by fitting model predictions to measured urea clearances. For all conditions of operation, a urea mass transfer coefficient of 0.014 cm/min successfully simulated the data. Predictions of blood flow, filtrate generation rate, and circuit pressure distribution were accurate. At lower dialysate flow rates, urea clearance approximated the sum of dialysate flow and filtration rate. At higher dialysate flows, however, departure from this ideal blood-dialysate equilibrium was observed. Model predictions regarding the relative contributions of diffusion and convection to urea clearance were explored. Under conditions of nearly perfect equilibration of urea between blood and dialysate at the blood inlet, the model predicts that the diffusive clearance of urea will increase with increasing rate of filtration and may exceed the rate of dialysate inflow.

Abstract

The effectiveness of insulin therapy on early diabetic nephropathy has not been established. In this study we examined the influence of continuous subcutaneous insulin on the progression of established nephropathy in streptozocin-induced diabetic rats. Normal controls and diabetic rats were studied for 11 mo. During the first 6 mo, all the diabetic rats received 2 U protamine zinc insulin s.c. twice weekly. During the last 5 mo of study, diabetic rats either continued on the occasional subcutaneous insulin regimen or received regular insulin by continuous subcutaneous infusion. Six months after the initiation of the study, the diabetic rats were severely hyperglycemic, and their relative mesangial areas had increased. Continued poor glycemic control in the rats receiving occasional insulin was associated with relative increased mesangial area (25.2 +/- 1.0% of glomerular area) and significant proteinuria (148 +/- 17 mg/24 h) compared with normal controls. In contrast, the use of continuous subcutaneous insulin therapy with improved glycemic control arrested mesangial changes (19.5 +/- 1.4% of glomerular area) and prevented the excessive proteinuria (71 +/- 13 mg/24 h). Indeed, these parameters did not differ from age-matched controls. We conclude that in the rat, continuous subcutaneous insulin therapy instituted after the development of early glomerular pathology is effective in arresting the disease process.

Abstract

In order to determine the degree to which blood and dialysate achieve equilibration of urea concentration during continuous arteriovenous hemodialysis (CAVHD), CAVHD circuits employing the Hospal AN69S dialyzer were perfused with bovine blood (85 to 90 ml/min, hematocrit 28%) containing 50 mg/dl of urea in the presence of countercurrent dialysate flowing at 10, 20, or 30 ml/min. The circuits were constructed and perfusion pressure (66 mmHg) set to yield a near zero net ultrafiltration rate. Urea clearances were measured and found to approximate the dialysate inflow rate, Qd, up to about 15 ml/min. At higher dialysate flow rates, equilibration was incomplete so that urea clearance was 24.7 +/- 0.5 (mean +/- SE) ml/min when Qd was 30 ml/min. A simplified model of urea transport in the dialyzer successfully simulated the data.

Abstract

The authors have studied the sequential changes in hemodynamic responses and Atrial Natriuretic Peptide (ANP) levels following bicarbonate hemodialysis with fluid removal followed by an infusion of saline and then ultrafiltration of the added fluid. Cardiac output, stroke volume, and thoracic fluid index (TFI) were measured by transthoracic impedence cardiography. Left cardiac work index (LCWI) was derived using these hemodynamic and mean arterial pressure (MAP) measurements. MAP was lower following dialysis when compared to pure ultrafiltration of a similar fluid loss. LCWI decreased during both dialysis and ultrafiltration. TFI, which is inversely related to intrathoracic fluid, increased following dialysis and ultrafiltration. ANP levels fell following fluid removal but remained elevated above normal control levels. The authors conclude that ANP levels are related to fluid not cardiac status in dialysis patients and that impedence cardiography is of value in determining hemodynamic and fluid changes during dialysis.

Abstract

In vitro and mathematical models of continuous arteriovenous hemofiltration (CAVH) have been developed. Human erythrocytes resuspended in normal saline containing 5% bovine albumin were used to perfuse the circuit from a gravity driven pressure source. Membrane hydraulic permeability was observed to decline from 31.2 x 10(-5) +/- 11.9 x 10(-5) cm/(min.mm Hg) before use to 12.3 x 10(-5) +/- 3.3 x 10(-5) (mean +/- SD) after use. This fall occurred during the first one to two hours whether perfused with blood or 5% albumin alone. Pressure-flow relationships of each circuit component, measured with 40% sucrose as a calibration medium, conformed to Poiseuille's equation. Use of high resistance blood access on the venous end of the circuit resulted in a low blood flow rate and high filtration fraction. The same access, when placed on the arterial end, produced both low blood flow rate and low filtration fraction. These results were a consequence of pressure distribution within the circuit as demonstrated by measurements of perfusion, prefilter, and postfilter pressures. The importance of negative pressure applied to the filter chamber in order to maintain favorable Starling forces, when the system was operated with a small bore arterial access, was demonstrated by similar methods. Enhancement of urea clearance by predilution was verified. Model simulations suggest that predilution will be of less benefit or even detrimental for other solutes which fail to distribute across the erythrocyte membrane. Comparison of results with predictions of a mathematical model demonstrated good agreement, but with some tendency to overestimate filtrate production. The latter was attributed to neglect of concentration polarization of plasma proteins in model development.